Short Bowel Syndrome (SBS) is a devastating clinical disorder that has a high prevalence of mortality and morbidity and takes a severe socioeconomic toll on patients. The hallmark of SBS is poor absorption of fluid and vital nutrients due to insufficient function or lack of large portions of the small intestine. Surgical and pharmacological means to enhance or grow the remaining intestinal tissue have thus far not been successful. In the U.S., the annual prevalence of patients requiring TPN due to SBS is approximately 12,000 per year. The annual cost of TPN is over $100,000 per year per patient. One potential long term treatment for SBS would be the development of a living, tissue engineered small intestinal graft to replace the lost tissue. The goal of this renewal grant is to use our existing biodegradable and biocompatible elastomers that can be tailored for specific soft tissue applications, to develop new approaches for treating intestinal defects. Previous scaffolds have not provided sufficient structural guidance to promote the regeneration of a fully biomimetic small intestinal tissue. A major limitation of previous approaches has been the lack of proper smooth muscle formation and intestinal motility and there has been a lack of morphological guidance to generate biomimetic tissue structures. In particular, given the unique multi-laminar and hierarchically-structured nature of small intestine, one promising new approach would be to microfabricate scaffolds from soft bioresorbable elastomers. We believe that these materials can be harnessed via microfabrication to create an in vitro model of small intestinal tissue that may also serve as a functional tissue engineered intestine, and a useful in vitro model for testing new drugs and other agents. Our overall hypothesis is that functional tissue engineering of small intestine requires microfabricated elastomeric scaffolds capable of guiding the formation of the mucosa and muscle layers and respective nutrient transport and peristalsis functions. We aim to: 1. Develop microfabricated elastomeric scaffolds for functional maturation of the mucosa layer of tissue engineered small intestine. 2. Investigate the use of microfabricated elastomeric scaffolds for functional maturation of the muscular is propria layer of tissue engineered small intestine. 3. Develop patches and tubes of microfabricated elastomeric scaffolds for functional maturation of mucosa and muscular is propria layers of tissue engineered small intestine and test in vivo. PUBLIC HEALTH RELEVANCE: The goal of this renewal grant is to use our existing biodegradable and biocompatible elastomers that can be tailored for specific soft tissue applications, to develop new approaches for treating intestinal defects. We will address the overall hypothesis that functional tissue engineering of biomimetic small intestine requires microfabricated elastomeric scaffolds capable of guiding the formation of the mucosa and muscular is propria layers.